Approximately 15 percent of patients recover from hepatitis C virus (HCV) infection while 85 percent become persistently infected with various degrees of associated chronic liver disease. In this study, comparisons will be made between patients who rapidly recover, those who have delayed recovery, those with persistent infection and stable chronic disease and those with rapidly progressive, fatal infection. The parameters measured will be viral burden (initially and over time), HCV genotype, the number of viral quasi-species (extent of viral heterogeneity) at the time of infection and subsequently, neutralizing antibody responses and, T-cell helper, proliferative and cytotoxic responses. The goal is to determine if any of these parameters can predict outcome. Studies to date have shown no correlation with genotype since the population is fairly homogeneous for HCV genotype 1. However, there does appear to be a correlation between viral quasi-species and disease outcome. Using rare specimens obtained during the first 16 weeks of HCV infection, we have measured the mean Hamming distance that reflects the extent of viral diversity (the degree of sequence divergence within the viral quasi-species). We have found that the mean Hamming distance 12 to 16 weeks after the onset of acute infection predicts whether the patient will recover from HCV infection or develop persistent infection and chronic liver disease. Patients who recover have a declining Hamming distance as antibody to HCV develops, signifying immunologic containment and then clearance of the virus. In contrast, the majority of patients demonstrate an increased mean hamming distance as antibody appears. This suggests that if the immune response is not sufficient to clear the virus, it paradoxically exerts immune pressure that results in mutations (escape variants) that lead to persistent infection. Interestingly, patients with fulminant hepatitis have a very low degree of viral diversity because they succumb to the infection before the immune system can clear the virus or exert immune pressure. This study has been published (Science 288:339-344.2000). In the next phase of this study, we are going to measure the quasi-species throughout the long-term course of HCV infection and the relation of the quasispecies to treatment responses.In addition we will identify patients with newly acquired or newly recognized hepatitis C so that we can serially measure viral load, viral quasi-species, neutralizing antibody responses and particularly, cell-mediated immune responses.Thus far studies have shown that patients with chronic HCV infection have impaired CD4 and CD8 cell responses to all HCV antigens function compared to patients who recover from acute HCV infection.We have also found that neutralizing antibodies do not correlate with recovery from acute HCV infection, but rather continue to increase in strength and breath of activity over the course of chronic infection. Despite thes antibodies, escape mutants continue to evade the immune response.